POLR2F

Chr 22

RNA polymerase II, I and III subunit F

Also known as: HRBP14.4, POLRF, RPABC14.4, RPABC2, RPB14.4, RPB6, RPC15

NCBI Gene: 5435 ENSG00000100142 UniProt: P61218 OMIM: 604414

The protein encoded by this gene is the sixth largest subunit of RNA polymerase II and serves as a common component of RNA polymerases I, II, and III, which are responsible for transcribing DNA into various types of RNA including mRNA, ribosomal RNA, and transfer RNA. Mutations in POLR2F cause autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and brain atrophy. The gene shows low constraint against loss-of-function variants, which is consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.88

Clinical Summary— POLR2F

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 37 VUS of 100 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.013

Z-score 1.87

OE 0.42 (0.22–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.89Z-score

OE missense 0.73 (0.59–0.90)

61 obs / 83.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.22–0.88)

0≤0.351.4

Missense OE?0.73 (0.59–0.90)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 5 / 12.0Missense obs/exp: 61 / 83.8Syn Z: 0.46

This gene — mechanism propensity

0.74top 25%

GOF

0.5169th %ile

LOF

0.2484th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.